Use of isoxazolin-3-one derivatives as antidepressants

ABSTRACT

A method of treating depression comprising administering to a patient an effective amount of a compound of the formula (Ib): ##STR1## wherein R 1b  is hydrogen, halogen, C 1  -C 4  alkyl, C 2  -C 4  alkenyl, C 2  -C 4  alkynyl, an unsubstituted benzyl group, a substituted benzyl having at least one substitutent (b) selected from the group consisting of C 1  -C 3  alkyl, C 1  -C 3  alkoxy, hydroxy, halogen, nitro, amino and C 2  -C 4  aliphatic carboxylic acylamino; unsubstituted phenyl or a substituted phenyl having at least one substitutent (b); R 2b  is hydrogen, C 1  -C 4  alkyl, unsubstituted phenyl, substituted phenyl having at least one substitutent (b), unsubstituted 5- or 6- membered heterocyclic having an oxygen, sulfur or nitrogen as a heteroatom, or substituted 5- or 6- membered heterocyclic having an oxygen, sulfur or nitrogen as a heteroatom and having at least one substitutent (b); and R 3b  and R 4b  are the same or different and each is hydrogen, C 1  -C 4  alkyl, unsubstituted benzyl, substituted benzyl having at least one substituent (b), unsubstituted phenyl, or substituted phenyl having at least one substitutent (b); or R 3b , R 4b  and the nitrogen atom to which they are attached together represent an alicyclic amino group having a total of 5 or 6 ring atoms, or which one ring atom is the nitrogen atom and one ring atom is optionally an additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, the alicyclic amino group being unsubstituted or, where there is an additional nitrogen heteroatom, the alicyclic amino group having a C 1  -C 3  alkyl substitutent on the additional nitrogen heteroatom; or a pharmacologically acceptable acid addition salt thereof.

This is a division of application Ser. No. 07/856494 filed Mar. 24, 1992(now U.S. Pat. No. 5,217,870), which is a division of application Ser.No. 07/537,517 field Jun. 13, 1990 (now U.S. Pat. No. 5,116,839).

BACKGROUND OF THE INVENTION

The present invention relates to isoxazoli-n-3-one derivatives of use asantidepressants.

Senile diseases are rapidly increasing with increase in the age of thepopulation. one such disease is senile depression. Indeed, the increasein suicide by the aged has become a social problem. Therefore, the needhas arisen to develop therapeutic agents for treating such diseases.

Typical available antidepressants include imipramine(10,11-dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine-5-propanamine), andmianserin hydrochloride(1,2,3,4,10,14b-hexahydro-2-methyldibenzo(c,f]pyrazino-(1,2-a)azepinehydrochloride). The need remains to develop further antidepressantcompounds.

SUMMARY OF THE INVENTION

The present invention provides a method of treating depression in apatient, which method comprises administering an effective amount of acompound having the formula (I): ##STR2## wherein: either (a)

the endocyclic dotted line ( ) is a single bond;

the exocyclic dotted line ( ) is a double bond;

A is oxygen;

B is a group of the formula (II) ##STR3## (wherein m is 0 and n is 0 or1;

R³, R⁴ and the nitrogen atom to which they are attached togetherrepresent an alicyclic amino group having a total of 5 or 6 ring atoms,of which one ring atom is said nitrogen atom and one ring atom isoptionally an additional heteroatom selected from nitrogen, oxygen orsulfur, said alicyclic amino group being unsubstituted or, where thereis an additional nitrogen heteroatom, said alicyclic amino group havinga substituent of a C₁ -C₃ alkyl group on said additional nitrogenheteroatom);

R¹ is a hydrogen atom or a halogen atom; and

R² is a phenyl group,,a substituted phenyl group having as substituentat least one substituent (a) selected from the following definition forsubstituent (a):

substituent (a): C₁₋₃ alkyl groups, C₁₋₃ alkoxy groups, halogen atoms,or a nitro group, a 5- or 6- membered heterocyclic group having one ormore oxygen, sulfur or nitrogen atom as heteroatoms, or a substituted 5-or 6- membered heterocyclic group having one or more oxygen, sulfur ornitrogen atom as heteroatoms and having at least one substituent (a);

or (b)

the endocyclic dotted line ( ) is a double bond;

the exocyclic dotted line ( ) is a single bond;

A is a group of the formula (II) ##STR4## (wherein m is 1 and n is 0;

R³ and R⁴ are be the same or different and each represents a hydrogenatom, a C₁ -C₄ alkyl group, a benzyl group, a substituted benzyl grouphaving at least one substituent (b) falling within the followingdefinition for substituent (b):

substituent (b): C₁ -C₃ C alkyl groups, a C₁ -C₃ alkoxy groups, ahydroxy group, halogen atoms, a nitro group, an amino group or C₂ -C₄aliphatic carboxylic acylamino groups;

a phenyl group, or a substituted phenyl group having one substituent(b); or

R³,R⁴ and the nitrogen atom to which they are attached togetherrepresent an alicyclic amino group having a total of 5 or 6 ring atoms,of which one ring atom is said nitrogen atom and one ring atom isoptionally an additional heteroatom selected from nitrogen, oxygen orsulfur, said alicyclic amino group being unsubstituted or, where thereis an additional nitrogen heteroatom, said alicyclic amino group havinga substituent of C₁ -C₃ alkyl group on said additional nitrogenheteroatom);

R¹ is a hydrogen atom, a halogen atom, a C₁ -C₄ alkyl group, a C₂ -C₄alkenyl group, a C₂ -C₄ alkynyl group, a benzyl group, a substitutedbenzyl group having at least one substituent (b), a phenyl group or asubstituted phenyl group having at least one substituent (b);

and R² is a hydrogen atom, a C₁ -C₄ alkyl group, a phenyl group, asubstituted phenyl group having at least one substituent (b), a 5- or 6-membered heterocyclic group having oxygen, sulfur or nitrogen atom asheteroatoms, or a substituted 5- or 6- membered heterocyclic grouphaving oxygen, sulfur or nitrogen atoms as heteroatoms having at leastone substituent (b);

or (c)

the endocyclic dotted line ( ) is a single bond;

the exocyclic dotted line ( ) is a double bond;

A is oxygen;

B is a group of the formula (II) ##STR5## (wherein m is 0 and n is 1;

R³, R⁴ and the nitrogen atom to which they are attached togetherrepresent an alicyclic amino group having a total of 5 or 6 ring atoms,of which one ring atom is said nitrogen atom and one ring atom isoptionally an additional heteroatom selected from nitrogen, oxygen orsulfur, said alicyclic amino group being unsubstituted or, where thereis an additional nitrogen heteroatom, said alicyclic amino group havinga substituent of C₁ -C₃ alkyl group on said additional nitrogenheteroatom);

R¹ and R², together with the carbon atoms to which they are attached,represent a phenyl ring fused to the isoxazoli ring or a substitutedphenyl ring fused to the isoxazoli ring, said substituted phenyl ringhaving as substituent at least one substituent selected fromsubstituents (b);

or a pharmacologically acceptable acid addition salt thereof.

It has already been reported that compounds within the general formula(I) are centrally-acting muscle relaxants (European PatentSpecifications 273744 and, 334674, published respectively on Jul. 6,1988 and Sep. 27, 1989) and that they can improve brain function(European Patent Specification 334674, mentioned above, and EuropeanPatent Specification 335723 published on Oct. 4, 1990).

PREFERRED EMBODIMENTS OF THE INVENTION

Within the different definitions (a), (b) and (c), R¹ is a hydrogenatom; a halogen atom, such as a fluorine, chlorine or bromine atom; a C₁-C₄ alkyl group, such as a methyl, ethyl, n-propyl, isopropyl n-butyl,isobutyl, or tert-butyl group; a C₂ -C₄ alkenyl group, such as a vinyl,allyl, 2-butenyl or 2-methylallyl group; a C₂ ∝C₄ alkynyl group, such asan ethynyl or 2-propynyl group; a benzyl group; a substituted benzylgroup having at least one substituent (b), which is one or more of analkyl group containing 1 to 3 carbon atoms such as a methyl, ethyl,n-propyl or isopropyl group, an alkoxy group containing 1 to 3 carbonatoms such as a methoxy, ethoxy, n-propoxy or isopropoxy group; ahalogen atom such as fluorine, chlorine or bromine; a nitro group, anamino group or an aliphatic acylamino group typically having 2 to 4carbon atoms, such as an acetylamino or propionylamino group; a phenylgroup or a substituted phenyl group having at least one substituent (b);

R² is a hydrogen atom, a C₁ -C₄ alkyl group, such as a methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl group; a phenylgroup, a substituted phenyl group having as substituent at least onesubstituent (a), which is one or more of an alkyl group containing 1 to3 carbon atoms such as a methyl, ethyl, n-propyl or isopropyl group, analkoxy group containing 1 to 3 carbon atoms such as a methoxy, ethoxy,n-propoxy or isopropoxy group, a halogen atom such as a fluorine.chlorine or bromine atom, or a nitro group, or the phenyl group havingas substituent at least one substituent (b), as the case may be; a 5- or6- membered heterocyclic group having one or more oxygen, sulfur ornitrogen atom as heteroatoms, such as a furyl, thienyl, thiazolyl orpyridyl group; or a substituted 5- or 6- membered heterocyclic grouphaving one or more oxygen, sulfur or nitrogen atom as heteroatoms andhaving at least one substituent (a) or substituent (b), as the case maybe;

or, R¹ and R², together with the carbon atoms to which they areattached. represent a phenyl ring fused to the isoxazoli ring or asubstituted phenyl ring fused to the isoxazoli ring. said substitutedphenyl ring having as substituent at least one substituent selected fromthe substituents (b);

R³, R⁴ and the nitrogen atom to which they are attached togetherrepresent an alicyclic amino group having a total of 5 or 6 ring atoms,of which one ring atom is said nitrogen atom and one ring atom isoptionally an additional heteroatom selected from nitrogen, oxygen orsulfur, said alicyclic amino group being unsubstituted or, where thereis an additional nitrogen heteroatom, said alicyclic amino group havinga substituent of a C₁ -C₃ alkyl group on said additional nitrogenheteroatom, and being illustrated by a morpholino, 1-piperazinyl,4-methyl-l-piperazinyl, 1-pyrrolidinyl or piperidino group;

or R³ and R⁴ are the same or different and each represents a hydrogenatom; a C₁ -C₄ alkyl group, such as those illustrated above; a benzylgroup, a substituted benzyl group having at least one substituent (b); aphenyl group; or a substituted phenyl group having one substituent (b).

In a preferred aspect, the present invention involves administering aneffective amount of a compound having the formula (Ia); ##STR6##wherein: R^(1a) is a hydrogen atom or a halogen atom;

R^(2a) is a phenyl group,.a substituted phenyl group having assubstituent at least one substituent (a), a 5-or 6- memberedheterocyclic group having one or more oxygen, sulfur or nitrogen atom asheteroatoms, or a substituted 5- or 6- membered heterocyclic grouphaving one or more oxygen, sulfur or nitrogen atom as heteroatoms andhaving at least one substituent (a); and

R³¹, R^(4a) and the nitrogen atom to which they are attached togetherrepresent an alicyclic amino group having a total of 5 or 6 ring atoms,of which one ring atom is said nitrogen atom and one ring atom isoptionally an additional heteroatom selected from nitrogen, oxygen orsulfur, said alicyclic amino group being unsubstituted or, where thereis an additional nitrogen heteroatom, said alicyclic amino group havinga substituent of a C₁ -C₃ alkyl group on said additional nitrogenheteroatom);

or a pharmacologically acceptable acid addition salt thereof.

In a further aspect, the present invention involves administering acompound of the formula (Ib): ##STR7## wherein: R^(1b) is a hydrogenatom, a halogen atom, a C₁ -C₄ alkyl group, a C₂ -C₄ alkenyl group, a C₂-C₄ alkynyl group, a benzyl group, a substituted benzyl group having atleast one substituent (b) falling within the following definition forsubstituent (b):

substituent (b): a C₁ `C₃ alkyl group, a C₁ -C₃ alkoxy group, a hydroxygroup, a halogen atom, a nitro group, an amino group or a C₂ -C₄aliphatic carboxylic acylamino group;

a phenyl group or a substituted phenyl group having at least onesubstituent (b);

R^(2b) is a hydrogen atom, a C₁ -C₄ alkyl group, a phenyl group, asubstituted phenyl group having at least one substituent (b), a 5- or 6-membered heterocyclic group having oxygen, sulfur or nitrogen atom asheteroatoms, or a substituted 5- or 6- membered heterocyclic grouphaving oxygen, sulfur or nitrogen atom as heteroatoms having at leastone substituent (b); and

R^(3b) and R^(4b) are be the same or different and each represents ahydrogen atom, a C₁ -C₄ alkyl group, a benzyl group, a substitutedbenzyl group having at least one substituent (b), a phenyl group, or asubstituted phenyl group having at least one substituent (b); or

R^(3b), R^(4b) and the nitrogen atom to which they are attached togetherrepresent an alicyclic amino group having a total of 5 or 6 ring atoms,of which one ring atom is said nitrogen atom and one ring atom isoptionally an additional heteroatom selected from nitrogen, oxygen orsulfur, said alicyclic amino group being unsubstituted or, where thereis an additional nitrogen heteroatom, said alicyclic amino group havinga substituent of C₁ -C₃ alkyl group on said additional nitrogenheteroatom); or a pharmacologically acceptable acid addition saltthereof.

In a yet further aspect, the present invention involves administering acompound of the formula (Ic): ##STR8## wherein: R^(1c) and R^(2c),together with the carbon atoms to which they are attached, represent aphenyl ring fused to the isoxazoli ring or a substituted phenyl ringfused to the isoxazoli ring, said substituted phenyl ring having assubstituent at least one substituent selected from substituents (b); and

R^(3c), R^(4c) and the nitrogen atom to which they are attached togetherrepresent an alicyclic amino group having a total of 5 or 6 ring atoms,of which one ring atom is said nitrogen atom and one ring atom isoptionally an additional heteroatom selected from nitrogen, oxygen orsulfur, said alicyclic amino group being unsubstituted or, where thereis an additional nitrogen heteroatom, said alicyclic amino group havinga substituent of C₁ -C₃ alkyl group on said additional nitrogenheteroatom;

or a pharmacologically acceptable acid addition salt thereof.

In the compounds of formula (Ia), R^(1a) represents a hydrogen atom or ahalogen atom such as a fluorine, chlorine or bromine atom.

R^(2a) can represent a phenyl group, which is unsubstituted or mayoptionally be substituted with at least one substituent, preferably oneor two substituents, where the substituents are chosen from substituents(a). The substituents (a) comprise an alkyl group containing 1 to 3carbon atoms such as a methyl, ethyl, n-propyl or isopropyl group, analkoxy group containing 1 to 3 carbon atoms such as a methoxy, ethoxy,n-propoxy or isopropoxy group, a halogen atom such as a fluorine,chlorine or bromine atom, or a nitro group. Particularly preferredsubstituents comprise one or two halogen atoms, especially one or twochlorine atoms. R^(2a) can represent a 5- or 6- membered heterocyclicgroup having one or more oxygen, sulfur or nitrogen atom as heteroatoms,preferably one heteroatom, or such a 5- or 6- membered heterocyclicgroup having at least one substituent (a), preferably one or two suchsubstituents. Examples of the heterocyclic group include a furyl,thienyl, thiazolyl or pyridyl group, and examples of the substituent (a)are given above in relation to R^(1a).

R^(3a) and R^(4a) and the associated nitrogen atom represent a 5- or6-membered alicyclic amino group such as a morpholino, 1-piperazinyl,4-methyl-l-piperazinyl, 1-pyrrolidinyl or piperidino group.

In the compounds of formula (Ib), R^(1b) can represent a hydrogen atom;a halogen atom such as a fluorine, chlorine or bromine atom; a straightor branched chain alkyl group containing 1 to 4 carbon atoms such as amethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butylgroup; a straight or branched chain alkenyl group containing 2 to 4carbon atoms such as a vinyl, allyl, 2-butenyl or 2-methylallyl group;an alkynyl group containing 2 to 4 carbon atoms such as an ethynyl or2-propynyl group; a benzyl group; a substituted benzyl group substitutedwith a substituent (b) (being an alkyl group containing 1 to 3 carbonatoms such as a methyl, ethyl, n-propyl or isopropyl group, an alkoxygroup containing 1 to 3 carbon atoms such as a methoxy, ethoxy,n-propoxy or isopropoxy group; a halogen atom such as fluorine, chlorineor bromine; a nitro group, an amino group or an aliphatic acylaminogroup typically having 2 to 4 carbon atoms, such as an acetylamino orpropionylamino group); or a phenyl group which is unsubstituted or mayoptionally be substituted with the substituents (b) as mentioned for thesaid benzyl group.

R^(2b) represents a hydrogen atom; a straight or branched chain alkylgroup containing 1 to 4 carbon atoms, as illustrated for the alkyl groupof R^(1b) ; a phenyl group which is unsubstituted or may optionally besubstituted with the substituents (b), as illustrated above; or anoptionally substituted 5- or 6-membered heterocyclic group containing anoxygen, sulfur or nitrogen atom such as furyl, thienyl, thiazolyl orpyridyl group, the optional substituents being substituents (b) asillustrated above.

Each of R^(3b) and R^(4b) represents a hydrogen atom; a straight orbranched chain alkyl group containing 1 to 4 carbon atoms as illustratedfor the alkyl group of R^(1b) ; a benzyl or phenyl group which isunsubstituted or may optionally be substituted with the substituents (b)as illustrated above, or R³ and R⁴ with the associated nitrogen atom mayrepresent a 5- or 6-membered alicyclic amino group such as a morpholino,1-piperazinyl, 4-methyl-l-piperazinyl, 1-pyrrolidinyl or piperidinogroup.

In the compounds of formula (Ic), R^(1c) and R^(2c), together with thecarbon atoms to which they are attached, represent a phenyl ring fusedto the isoxazoli ring or a substituted phenyl ring fused to theisoxazole ring. The substituted phenyl ring has as substituent at leastone substituent selected from C₁ -C₃ alkyl groups, C₁ -C₃ alkoxy groups,hydroxy groups, halogen atoms, nitro groups, amino groups or C₂ ∝C₄aliphatic carboxylic acylamino groups. Such groups are illustrated abovewith reference to substituents (b).

R^(3c), R^(4c) and the nitrogen atom to which they are attached togetherrepresent an alicyclic amino group having a total of 5 or 6 ring atoms,of which one ring atom is said nitrogen atom and one ring atom isoptionally an additional heteroatom selected from nitrogen, oxygen orsulfur. The alicyclic amino group is unsubstituted or, where there is anadditional nitrogen heteroatom, it can have a C₁ -C₃ alkyl group on theadditional nitrogen heteroatom. Suitable examples comprise a morpholino,1-piperazinyl, 4-methyl-l-piperazinyl, 1-pyrrolidinyl or piperidinogroup.

Particularly preferred compounds are of formula (Ia), wherein R^(1a) isa hydrogen atom or a halogen atom, especially a hydrogen atom; R^(2a) isa phenyl group or a substituted phenyl group having as substituent oneor two substituents, more especially one or two halogen atoms, forexample a substituted phenyl group having as substituent one or twochlorine atoms; R^(3a), R^(4a) and the nitrogen atom to which they areattached together represent a morpholino group; and pharmacologicallyacceptable acid addition salts thereof, especially the hydrochlorideaddition salts thereof.

Pharmacologically acceptable acid addition salts of the isoxazolin-3-onederivatives of the said general formula (I) include, for example, saltsof a mineral acid such as a hydrochloride, hydrobromide or sulfate salt,or salts of an organic acid such as an oxalate, lactate, citrate,tartarate, succinate, maleate, fumarate or methanesulfonate salt.

The compounds of the said general formula (I) exist as optical isomers,owing to the presence of at least one asymmetric carbon atom. Thepresent invention extends to such isomers and mixtures thereof,including racemic mixtures.

Examples of preferred compounds of the general formula (I) include thefollowing list of compounds which are numbered in sequence for furtherreference, and pharmaceutically acceptable salts of these compounds,especially the hydrochlorides of these compounds. In the list, forcompounds of formula (Ia) where R^(3a) and R^(4b) form an alicyclicamino group with the nitrogen to which they are attached, there is asingle entry under R^(3a) and R^(4a). Similar considerations apply tothe substituents of compounds of the other formulae.

In the list, the following abbreviations are employed:

    ______________________________________                                               Phe         phenyl                                                            Pyrd        pyrrolidinyl                                                      Mor         morpholino                                                        Piz         piperazinyl                                                       Me          methyl                                                            Pip         piperidyl                                                         Nox         nitro                                                             MeO         methoxy                                                           Thi         thienyl                                                           Et          ethyl                                                             Pr          propyl                                                            iPr         isopropyl                                                         Bu          butyl                                                             iBu         isobutyl                                                          sBu         sec-butyl                                                         tBu         tert-butyl                                                        Hex         hexyl                                                             Bz          benzyl                                                            All         allyl                                                             Buen        butenyl                                                           Pryn        propynyl                                                   ______________________________________                                        Compounds of formula (Ia):                                                     ##STR9##                    (Ia)                                             No.       R.sup.1a  R.sup.2a    R.sup.3a                                                                           R.sup.4a                                 ______________________________________                                         1        H         Phe         1-Pyrd                                         2        H         Phe         Mor                                            3        H         Phe         1-Piz                                          4        H         Phe         4-Me-1-Piz                                     5        H         Phe         1-Pip                                          6        Cl        Phe         1-Pyrd                                         7        Cl        Phe         Mor                                            8        Cl        Phe         1-Piz                                          9        Cl        Phe         4-Me-1-Piz                                    10        Cl        Phe         1-Pip                                         11        H         4-ClPhe     Mor                                           12        H         3-ClPhe     Mor                                           13        H         4-NoxPhe    Mor                                           14        H         4-MeOPhe    Mor                                           15        H         3-MeOPhe    Mor                                           16        H         2-MeOPhe    Mor                                           17        H         4-OHPhe     Mor                                           18        H         4-FlPhe     Mor                                           19        H         2,4-diClPhe Mor                                           20        H         2-Thi       Mor                                           21        H         3-Pyr       Mor                                           22        H         (S)-4-ClPhe Mor                                           ______________________________________                                        Compounds of formula (Ib):                                                     ##STR10##                   (Ib)                                             No.       R.sup.1b  R.sup.2b    R.sup.3b                                                                           R.sup.4b                                 ______________________________________                                        23        H         Phe         H    H                                        24        H         Phe         H    Me                                       25        H         Phe         H    Et                                       26        H         Phe         H    Pr                                       27        H         Phe         H    iPr                                      28        H         Phe         H    Bu                                       29        H         Phe         H    iBu                                      30        H         Phe         H    sBu                                      31        H         Phe         H    Hex                                      32        H         Phe         H    Phe                                      33        H         Phe         H    Bz                                       34        H         Phe         Me   Me                                       35        H         Phe         1-Pyrd                                        36        H         Phe         Mor                                           37        H         Phe         1-Piz                                         38        H         Phe         4-Me-1-Piz                                    39        H         Phe         1-Pip                                         40        Cl        Phe         H    H                                        41        Cl        Phe         H    Me                                       42        Cl        Phe         H    Et                                       43        Cl        Phe         H    Pr                                       44        Cl        Phe         H    iPr                                      45        Cl        Phe         H    Bu                                       46        Cl        Phe         H    iBu                                      47        Cl        Phe         H    sBu                                      48        Cl        Phe         H    tBu                                      49        Cl        Phe         H    Phe                                      50        Cl        Phe         H    Bz                                       51        Cl        Phe         Me   Me                                       52        Cl        Phe         1-Pyrd                                        53        Cl        Phe         Mor                                           54        Cl        Phe         1-Piz                                         55        Cl        Phe         4-Me-1-Piz                                    56        Cl        Phe         1-Pip                                         57        Me        Phe         H    H                                        58        Me        Phe         Mor                                           59        iPr       Phe         Mor                                           60        iBu       Phe         Mor                                           61        All       Phe         Mor                                           62        2-Buen    Phe         Mor                                           63        2-Pryn    Phe         Mor                                           64        Phe       Phe         Mor                                           65        Bz        Phe         Mor                                           66        H         H           Mor                                           67        H         Et          H    H                                        68        H         Me          Mor                                           69        H         Pr          Mor                                           70        H         iPr         Mor                                           71        H         Bu          Mor                                           72        H         iBu         Mor                                           73        H         sBu         Mor                                           74        H         tBu         Mor                                           75        Cl        Me          Mor                                           76        H         4-ClPhe     Mor                                           77        H         3-ClPhe     Mor                                           78        H         4-NoxPhe    Mor                                           79        H         4-MeOPhe    Mor                                           80        H         3-MeOPhe    Mor                                           81        H         2-MeOPhe    Mor                                           82        H         4-OHPhe     Mor                                           83        H         4-FlPhe     Mor                                           84        H         2,4-diClPhe Mor                                           85        H         2-Thi       Mor                                           86        H         3-Pyr       Mor                                           ______________________________________                                        Compounds of formula (Id):                                                     ##STR11##                   (Id)                                             No.     R.sup.3d                                                                             R.sup.4d R.sup.5                                                                            R.sup.6  R.sup.7                                                                            R.sup.8                            ______________________________________                                        86      H      H        H    H        H    H                                  87      H      H        H    Cl       H    H                                  88      H      Et       H    H        H    H                                  89      H      Pr       H    H        H    H                                  90      H      iPr      H    H        H    H                                  91      H      Bu       H    H        H    H                                  92      H      iBu      H    H        H    H                                  93      H      sBu      H    H        H    H                                  94      H      tBu      H    H        H    H                                  95      H      Phe      H    H        H    H                                  96      H      Bz       H    H        H    H                                  98      Me     Me       H    H        H    H                                  99      1-Pyrd          H    H        H    H                                  100     Mor             H    H        H    H                                  101     1-Piz           H    H        H    H                                  102     4-Me-1-Piz      H    H        H    H                                  103     1-Pip           H    H        H    H                                  104     H      Me       H    H        H    Cl                                 105     H      Et       H    H        H    Cl                                 106     H      Pr       H    H        H    Cl                                 107     H      iPr      H    H        H    Cl                                 108     H      Bu       H    H        H    Cl                                 109     H      iBu      H    H        H    Cl                                 110     H      sBu      H    H        H    Cl                                 111     H      tBu      H    H        H    Cl                                 112     H      Phe      H    H        H    Cl                                 113     H      Bz       H    Cl       H    H                                  114     H      Me       H    Cl       H    H                                  115     1-Pyrd          H    Cl       H    H                                  116     Mor             H    Cl       H    H                                  117     1-Piz           H    Cl       H    H                                  118     4-Me-1-Piz      H    Cl       H    H                                  119     1-Pip           H    Cl       H    H                                  120     H      H        H    Cl       H    H                                  121     H      H        H    H        H    Me                                 122     H      H        H    NH.sub.2 H    H                                  123     H      H        H    NHCOCH.sub.3                                                                           H    H                                  124     H      H        H    OMe      H    H                                  ______________________________________                                    

Compounds 2, 11, 12, 18, 19 and 22, and their hydrochlorides arepreferred, with Compounds 11 and 22 and their hydrochlorides being mostpreferred.

It has been shown by pharmacological tests that the compounds of thesaid general formula (I) according to the present invention exhibitanti-reserpine activity and the penetration of spontaneous locomotionupon administration of monoamine precursors such as L-DOPA and L-5-HTP.The procedure employed in the tests will be explained concretely below:

1 . Effect on reserpine-induced posies in the mouse

Male ddY mice (4 weeks of age, body weight 22-27 g) were used, dividedinto the indicated groups each consisting of 3 or 6 animals. The testcompounds were dissolved or suspended in an appropriate solvent(physiological saline, 0.5% CMC or 1% dimethylsulfoxide solution) andwere orally administered immediately before treatment with reserpine.The animals of the control groups were given corresponding vehicles in asimilar manner. A reference compound, imipramine. hydrochloride, wasalso dissolved in physiological saline and administered in a similarmanner.

The vials containing the test solutions were labeled with coded ciphersand the administration was carried out in randomized order. The scorertherefore did not know which samples had been given to which mice.

The mice were then subcutaneously treated with reserpine at a dose of 2mg/kg. After 90 minutes, the extent of ptosis was scored. Grading of thescore was based on the shape of eye immediately after the mice weretaken out from their cages;

    ______________________________________                                        0             round eye shape, as normal                                      1             1/3 eyelid closing                                              2             2/3 eyelid closing                                              3             closed eyelid.                                                  ______________________________________                                    

The inhibition rate at each dose was calculated from the scoresaccording to the following equation: ##EQU1## The inhibition rate wasthen scored on the following basis:

    ______________________________________                                               inhibition rate                                                                        score                                                         ______________________________________                                               71% or more                                                                            +                                                                    41% to 70%                                                                             ±                                                                 40% or less                                                                            -                                                             ______________________________________                                    

Results on antagonism against reserpine-induced ptosis in mice

    ______________________________________                                                    Dosage   Number    Inhibition                                     Compound    (mg/kg)  of mice   rate (%)                                                                             Score                                   ______________________________________                                        Compound 11  3       6         50     ±                                    Compound 11 10       6         56     ±                                    Compound 11 30       6         72     +                                       Compound 22  3       6         56     ±                                    Compound 22 10       6         81     ±                                    Compound 22 30       6         100    +                                       Compound 36 100      3         71     +                                       Compound 53 30       3         55     ±                                    Compound 76 100      3         71     +                                       Compound 87 30       3         75     +                                       Compound 87 100      3         100    +                                       Imipramine.HCl                                                                            30       6         61     ±                                    ______________________________________                                    

2. Potentisting effect of compounds upon spontaneous locomotoractivities in mice treated with L-DOPA

Male ddY mice .(5 weeks old, body weight 30-33 g) were used, afterdivided into groups each consisting of 5 animals (experiment 1) or 15animals (experiment 2). The test compounds were prepared as described inthe anti-reserpine study. and given orally 20 minutes beforeadministration of MK-486. In control animals, saline was similarlyadministered. fn order to prevent decomposition of L-DOPA at theperipheral site, the mice were intraperitoneally given MK-486(carbidopa) at a dose of 20 mg/kg and treated intraperitoneally 30minutes later with L-DOPA. The mice were placed in a cage on a locomotoractivity counter (AUTOMEX-11). one-by-one (experiment 1) or 3 mice acage (experiment 2). Spontaneous locomotor activities were determinedfor an hour, and the average locomotor activity at each dose wascalculated from 5-counts. The spontaneous locomotor activity i-n animalstreated with the compound was statistically analyzed versus the controlgroup using Student's two-tailed-t-test.

Results of potentiating effects of compounds upon spontaneous locomotoractivities in mice given L-DOPA

    ______________________________________                                                                   Average locomotor                                           Dose     Number   activities                                         Compound (mg/kg)  of mice  (+/-S.E.)   P                                      ______________________________________                                        Control  --        5        160(+/-128)                                       Compound 11                                                                            50        5       3355(+/-878)                                                                              <0.05                                  Control  --       15        666(+/-137)                                       Compound 22                                                                            50       15       6013(+/-629)                                                                              <0.001                                 ______________________________________                                    

As shown, Compound 11, and particularly its (S) isomer which is Compound22, significantly increased the spontaneous locomotor activity withtreatment of L-DOPA at a dose of 50 mg/kg.

3. Potentisting effect of compounds upon .spontaneous locomotoractivities in mice treated with L-5-HTP

Male ddY mice (4 weeks old, body weight 22-25 g) were used, afterdivided into groups each consisting of 15 mice. Before administration ofMK-486 (20 mg/kg, IP), either the test compound formulation or vehicle(control group) was orally administered. At 30 min after administrationof MK-485, L-5-HTP (100 mg/kg IP) was injected. Spontaneous locomotoractivities were determined from 15 minutes after L-5-HTP. For thisdetermination, 3 mice were placed in a locomotor counter (Automex) foran hour and the total count noted. Five such apparatuses were used foreach dose, in order to eliminate different sensitivities of eachapparatus. Thus, 15 mice were used in total for each dose. The averagecount and SE were calculated from the 5 determinations for each dose,and statistically analyzed versus control group using Student'stwo-tailed t-test.

Results of potentiating effects of compounds upon spontaneous locomotoractivities in mice given L-DOPA

    ______________________________________                                                 Dose       Average spontaneous                                       Compound (mg/kg)    locomotor activity                                                                           P                                          ______________________________________                                        saline   --         2147(+/-334)                                              Compound 22                                                                            3          3544(+/-318)   <0.01                                      ______________________________________                                    

As shown, Compound 22, which is the (S) isomer of Compound 11,significantly potentiated (P<0.01) the spontaneous locomotor activity ontreatment with L-5-HTP at a dose of 3 mg/kg.

4. Acute toxicity

Each of the Compounds 11, 36 (as its hydrochloride), 53, 76, and 87dissolved in a 0.5% CMC solution was orally administered to 5 mice at adose of 300 mg/kg. Observations were made for a period of 5 days. Noparticular symptoms were detected and all the mice survived.

From these results, it can be seen that the compounds of the generalformula (I) show low toxicity without inducing drowsiness, and exhibitan antidepressant activity, such as an anti-reserpine activity and aL-DOPA promoting activity. Furthermore, there is evidence to suggestthat the present compounds do not show the anticholinergic activitywhich is apparently exerted by imipramine, and have a considerablydifferent mode of action to mianserin.

The compounds can be administered clinically by the parental route or bythe oral route. They exhibit good absorbability by the oral route,especially since the hydrochloride or other salt is soluble in water. Byway of example, the oral route include the form of tablets, capsules,granules, powders, syrups or the like, and suitable formulations for theparenteral route include injections, suppositories or the like.

The pharmaceutical preparations of this invention can be producedaccording to the conventional manner using the adjuvants generally knownin the art of the field, such as one or more of an excipient, binder,disintegrator, lubricant, corrective or the like. The dosage may varydepending upon the symptom, age, body weight and other factors relatingto the patient, but in case of oral administration to adults, the activecompound is usually administered at a dose of from 3 mg to 100 mg(especially 10-50 mg) once to three times a day.

Isoxazolin-3-one derivatives of the general formula (1). and saltsthereof, can be prepared by methods already reported in the literature.For example, the compounds can be prepared by adoption of methods andstarting materials described in European Patent Specification 273744,European Patent Specification 334674, European Patent Specification335723, Japanese Patent Provisional Publication No. Sho56-34674,Japanese Patent Provisional Publication No. Sho 52-31070, andJapanese Patent Provisional Publication No. Sho 55-013766, among others,the disclosure o,, which is incorporated by reference.

EXAMPLES OF THE INVENTION

The following Examples illustrate the preparation of typical compoundsof the invention from known starting compounds or from startingcompounds which may be prepared using procedures analogous to thoseemployed for known compounds. Formulation Examples are also given. AReference Example is also included for the preparation of a startingcompounds.

Example 1 (S)-5-(P-Chlorohenyl)-2-(2-hydroxy-3-morpholinor)ropyl)-isoxazolin-3-one hydrochloride1-(a): Chloro-2-hydroxypropyl)-5-(p-chloro-phenyl)-isoxazolin-3-one

5-(P-Chlorophenyl)-3-hydroxyisoxazole (80.0g) was slowly added at 80° C.to a toluene solution (80ml) of (R)-(-)epichlorohydrin (50.0g), and thereaction solution was stirred for 20 hours at 80°-85° C. After coolingthe reaction solution, the deposited crystalline precipitate was washedwith cold toluene (200ml) to give 85.8g of the desired product.

Yield 72. 8%, melting point 135° to 136° C.

Elemental Analysis, C₁₂ H₁₁ NO₃ Cl₂ : calcd: C, 50.02; H, 3.85; N, 4.86;Cl, 24.61. found: C, 50.09; H, 3.98; N, 4.89; Cl, 24.55.

IR spectra γmax (KBr) cm⁻¹ : 3231, 1642, 1628.

NMR spectra (CDCl₃) δ ppm: 3.56-3.76 (2H, multiplet), 4.10-4.40 (3H,multiplet), 6.05 (1H, singlet), 7.48 (2H, doublet, J=9.0 Hz), 7.60 (2H,doublet, J=9.0 Hz).

1-(b):(S)-5-(P-Chlorophenyl)-2-(2-hydroxy-3-morphol-inopropyl)isoxazolin-3-one

In an ethanol solution (800ml) of 80. 0 q of the product of step 1-(a),morpholine (29. Og) and potassium carbonate (46.0g) were refluxed for 6hours. After cooling, the reaction solution was concentrated underreduced pressure, and the resulting residue was dissolved in ethylacetate (800ml), then washed with 10% sodium chloride solution, anddried over anhydrous magnesium sulfate. After concentration of thereaction solution under reduced pressure, the resulting solid wasrecrystallized with ethyl acetate to give 84.3g of the desired product.

Yield 89.8%, melting point 121° to 123° C.

Elemental Analysis, C₁₆ H₁₉ N₂ O₄ Cl: calcd: C, 56.72; H, 5.65; N, 8.27;Cl, 10.46. found: C, 56. 69; H, 5.77; N, 8.14; Cl, 10.19.

IR spectra λmax (KBr) cm⁻¹ : 3326, 1655, 1636.

NMR spectra (CDCl₃) δ ppm: 2.40-2.75 (2H×3, multiplat), 3.72 (2H×2,triplet, J=6.0 Hz), 6.02 (1H, singlet), 7.46 (2H, doublet, J=9.0 Hz),7.60 (2H, doublet, J=9. 0 Hz).

1-(c):(S)-5-(p-Chlorophenyl)-2-(2-hydroxy-3-morphol-inopropyl)isoxazolin-3-onehydrochloride

4N-HC1/dioxane (50ml) was slowly dropped in an ethanol solution (600ml)of 60.0 g of the product of step 1-(b) at 5° C., and the reactionsolution was stirred for 5 minutes. After concentration of the reactionsolution under reduced pressure, the resulting solid was recrystallizedwith ethanol to give 61.5g of the desired product.

Yield 92.5%, melting point 210°-213° C. (decompd.)

Elemental Analysis, C₁₆ H₂₀ N₂ O₄ Cl₂ : calcd: C, 51.21; H, 5.37; N,7.47; Cl, 18.90. found: C, 51.15; H, 5.27; N, 7.59; Cl, 18.66.

IR spectra λmax (KBr) cm⁻¹ : 3266, 1671.

NMR spectra (CDCl₃) δ ppm: 3.05-40 (2H×5, multiplet), 3.95 (1H, doublet,J=2.4Hz), 3.97 (1H, singlet), 4.33-4. 43 (1H, multiplet), 6.07 (1H,singlet), 7.33(2H, doublet, J=9.0 Hz), 7.60 (2H, doublet, J=9.0 Hz).

²³ [a]_(D) -2.0° (c=1.0, H₂ O).

Example 23-(2-Hydroxy-3-morpholinopropoxy)-5-phenylisoxazole.hydrochloride 2-(a):3-(2-Hydroxy-3-morpholinogropoxy)-5-phenylisoxazole

To a solution of 40.0 g of 3-(2,3-epoxypropoxy)-5-phenylisoxazoledissolved in ethanol (400 ml) was added 17.6 g of morpholine and themixture was refluxed by heating for 5 hours, followed by concentrationunder reduced pressure. The resulting solid was recrystallized fromethyl acetate to afford 50.0 g of the title compound with melting point123°-124° C. as colorless columns.

IR spectrum (KBr) cm⁻¹ : 3190, 1624, 1511, 1440

NMR spectrum (CDCl₃ ppm: 2.30-2.85 (2H×3, multiplet), 3.20-3.70 (1H,broad), 3.73 (2H×2, triplet, J=4.5), 3.90-4.55 (1H, multiplet),4.15-4.50, (2H, multiplet), 6.18 (1H, singlet), 7.35-7.85 (5H,multiplet)

2-(b):3-(2-Hydroxy-3-morpholinopropoxy)-5-phyenyl-isoxazole.hydrochloride

To a solution of 5.00 g of3-(2-hydroxy-3-morpholinopropoxy-5-phenylisoxazole dissolved in ethylacetate (200 ml) was added a 4N HC1/dioxane solution (5.0 ml) and themixture was stirred at room temperature for 10 minutes. The reactionmixture was concentrated under reduced pressure to afford 5.21 g of thetitle compound with melting point 149°-150° C. as colorless powderycrystals.

IR spectrum (KEr) cm⁻¹ : 3215, 1625, 1513, 1461

NMR spectrum (D₂ O) δ ppm: 3.66-4.13 (2H'3, multiplet), 4.50 (2H×2,triplet, J=4.5), 4.69 (2H, doublet J=4.5), 4.80-5.20 (1H, multiplet),6.83 (1ZH, singlet), 7.80-8.30 (5H, multiplet).

Examples 3 to 8

Following a similar procedure to that of Example 2, the compounds ofExamples 3 to 8 listed below were synthesized.

    ______________________________________                                                                      Melting                                         Example                                                                              Compound               Point (°C.)                              ______________________________________                                        3      4-Chloro-3-(2-hydroxy-3-morpholino-                                                                  75-76                                                  propoxy)-5-phenylisoxazole                                             4      5-(p-Chlorophenyl)-3-(2-hydroxy-3-                                                                   114-115                                                morpholinopropoxy)isoxazole                                            5      3-(3-n-Hexylamino-2-hydroxypropoxy)-                                                                 115-116                                                5-phenylisoxazole                                                      6      5-(m-Chlorophenyl)-3-(2-hydroxy-3-                                                                   76-77                                                  morpholinopropoxy)isoxazole                                            7      4-Chloro-3-(2-hydroxy-3-morpholino-                                                                  200-202                                                propoxy)-5-phenylisoxazole.HCl                                                                       (decomp.)                                       8      3-(2-Hydroxy-3-morpholinopropoxy)-                                                                   94-95                                                  4-methyl-5-phenylisoxazole                                             ______________________________________                                    

Example 92-(3-Carbamoyloxy-2-hydrophopyl)-5-chlorobenzoisoxazol-in-3-one

To a solution of 1.00 g of5-chloro-2-(2,3-dihydroxypropyl)-1,2-benzoisoxazolin-3-one intetrahydrofuran (20 ml) was added 0.40 g of trichloromethylchloroformate and the mixture was stirred at room temperature. After 30minutes, the reaction mixture was cooled to 5° C. followed by addingdropwise 0.42 g of triethylamine. After stirring at the same temperaturefor 30 minutes, 5.0 ml of a 28% ammonia solution was added. Furthermore,after stirring at room temperature for 2 hours, the reaction mixture wasrefluxed by heating for 3 hours followed by concentration under reducedpressure. The residue was dissolved in ethyl acetate (100 ml) and thesolution was washed with a 10% NaCl solution. The organic layer wasdried over anhydrous magnesium sulfate and the drying agent was removedby filtration. The solvent was distilled off under reduced pressure andthe residue was purified by column chromatography (developing solvent:ethyl acetate) through silica gel to afford 0.75 g (64.1%) of the titlecompound having melting point 161°-162° C. as a colorless powder.

IR spectrum (KBr) cm⁻¹ : 3420, 3320, 3260, (OH, NH₂), 1683, 1662 (C=O)

NMR spectrum (DMSO-d₆)δ ppm: 3.86-4.46 (5H, broad), 5.31 (1H, doublet,J=4.5), 6.50 (2H, singlet), 7.46-7.90 (3H, multiplet)

    ______________________________________                                        Formulation Example 1                                                         Tablets                                                                       ______________________________________                                        5-p-chlorophenyl-2-(2-hydroxy-3-                                                                       10.0 mg                                              morpholinopropyl)-4-isoxazolin-3-one                                          lactose                  83.3 mg                                              corn starch              25.0 mg                                              HPC (Nippon Soda Co., Ltd.)                                                                            1.2 mg                                               magnesium stearate       0.5 mg                                               Total                    120 mg                                               ______________________________________                                    

Adopting a conventional procedure, tablets each weighing 120 mg weremade from the ingredients comprising the above formulation.

    ______________________________________                                        Formulation Example 2                                                         Capsule                                                                       ______________________________________                                        3-(2-hydroxy-3-morpholinopropoxy)-                                                                     25.0 mg                                              5-phenylisoxazole.hydrochloride                                               lactose                  153.6 mg                                             corn starch              100.0 mg                                             magnesium stearate       1.4 mg                                               Total                    280.0 mg                                             ______________________________________                                    

The powders of the above prescription were mixed, passed through a 60mesh sieve, and 280 mg portions of the resulting powder was packet intoNo. 3 gelatin capsules.

    ______________________________________                                        Formulation Example 3                                                         Capsule                                                                       ______________________________________                                        2-(3-carbamoyloxy-2-hydroxypropyl)-5-                                                                   25.0 mg                                             chlorobenzoisoxazolin-S-one                                                   lactose                   153.6 mg                                            corn starch               100.0 mg                                            Magnesium stearate        1.4 mg                                              Total                     280.0 mg                                            ______________________________________                                    

The starch powder in the above prescription was mixed, passed through a60 mesh sieve, and 280 mg portions of the resulting powder was packedinto No. 3 gelatin capsules.

Reference Example 1 3-(2,3-Epoxypropoxy)-5-henylisoxazole

To a solution of 10.00 g of 3-hydroxy-5-henylisoxazole dissolved inhexamethylphosphoroamide (50ml) were added 10.28 g of anhydrouspotassium carbonate and 6.89 g of epichlorohydrin, and the mixture wasstirred at room temperature for 24 hours. After insoluble materials inthe reaction mixture were removed by filtration, the filtrate wasdiluted with ethyl acetate (200 ml) followed by washing with an aqueous10% sodium chloride solution (200 ml×2). After the organic layer wasdried over anhydrous magnesium sulfate, the drying agent was filteredoff and the filtrate was freed from the solvent by distillation underreduced pressure. The residue was purified by column chromatographythrough silica gel (developing solvent: a 4:1 mixture of cyclohexane andethyl acetate) to afford 11.00 g (82.0%) of the title compound withmelting point 98° to 99° C. as colorless needles.

IR spectrum (KBr) cm⁻¹ : 615, 1585, 1511, 1459, 1418

NMR spectrum (CDCl₃) δ ppm: 2.73 (1H, AB-doublet of doublets, J=4.5,3.0), 2.87 (1H, AB-doublet of-doublets, J=4.5, 4.5), 3.26-3. 50 (1H,multiplet), 4.20 (1H, AB-doublet of doublets, J=12.0, 6.0), 4.58, (1H,AB-doublet of doublets, J 12.0, 3.0), 6.20 (1H, singlet), 7.30-7.90 (5H,multiplet).

We claim:
 1. A method of treating depression in a patient, which methodcomprises administering to a patient in need thereof an effective amountof a compound of the formula (Ib): ##STR12## wherein: R^(1b) is ahydrogen atom, a halogen atom, a C₁ -C₄ alkyl group, a C₂ -C₄ alkenylgroup, a C₂ -C₄ alkynyl group, an unsubstituted benzyl group, asubstituted benzyl group having at least one substituent (b), saidsubstituent (b) being selected from the group consisting of a C₁ -C₃alkyl group, a C₁ -C₃ alkoxy group, a hydroxy group, a halogen atom, anitro group, an amino group and a C₂ -C₄ aliphatic carboxylic acylaminogroup;an unsubstituted phenyl group or a substituted phenyl group havingat least one substitutent (b); R^(2b) is a hydrogen atom, a C₁ -C₄ alkylgroup, an unsubstituted phenyl group, a substituted phenyl group havingat least one substitutent (b), a 5- or 6- membered heterocyclic grouphaving an oxygen, sulfur or nitrogen atom as heteroatoms, or asubstituted 5- or 6- membered heterocyclic group having an oxygen,sulfur or nitrogen atom as heteroatoms and having at least onesubstituent (b); and R^(3b) and R^(4b) are the same or different oneeach is a hydrogen atom, a c₁ -C₄ alkyl group, an unsubstituted benzylgroup, a substituted benzyl group having at least one substituent (b),an unsubstituted phenyl group, or a substituted pehnyl group having atleast one substituent (b); or R^(3b), R^(4b) and the nitrogen atom towhich they are attached together represent an alicyclic amino grouphaving a total of 5 or 6 ring atoms, of which one ring atom is saidnitrogen atom and one ring atom is optionally an additional heteroatomselected from the group consisting of nitrogen, oxygen and sulfur, saidalicyclic amino group being unsubstituted or, where there is anadditional nitrogen heteroatom, said alicyclic amino group having asubstitutent of a C₁ -C₃ alkyl group on said additional nitrogenheteroatom; or a pharmacologically acceptable acid addition saltthereof.
 2. The method according to claim 1, wherein R^(1b) is hydrogen,fluorine, chlorine, romine, methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, tert-butyl, vinyl, allyl, 2-butenyl, 2-methylallyl, ethynyl,2-propynyl, unsubstituted benzyl, unsubstituted phenyl or benzyl orphenyl substituted by at least one substituent selected from the groupconsisting of methyl, ethyl, n--ropyl, isopropyl, methoxy, etoxy,n-propoxy, isopropoxy, fluorine, chlorine, bromine, nitro, amino,acetylamino and propionylamino; R^(2b) is hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, unsubstitutedphenyl, phenyl substituted by at least one substitutent selected fromthe group consisting of methyl, ethyl, n-propyl, isopropyl, methoxy,ethoxy, n-ropoxy, isopropoxy, fluorine, chlorine, bromine, nitro, amino,acetylamino and propionylamino, or R^(2b) is a heterocyclic selectedfrom the group consisting of furyl, thienyl, thiazolyl and pyridyl,wherein said heterocyclic is unsubstituted or unsubstituted by at leastone substituent selected from the group consisting of methyl, ethyl,n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluorine,chlorine, bromine, nitro, amino, acetylamino and propionylamino, R^(3b)and R^(4b) are the same or different and each is hydrogen, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, unsubstitutedphenyl or phenyl substituted by at least one substituent selected fromthe group consisting of methyl, ethyl, n-porppyl, isopropyl, methoxy,ethoxy, n-propoxy, isopropoxy, fluorine, chlorine, bromine, nitro,amino, acetylamino and propionylamino, unsubstituted benzyl or benzylsubstituted by at least one substitutent selected from the groupconsisting of methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy,n-propoxy, isopropoxy, fluorine, chlorine, bormine, nitro, amino,acetylamino and propionylamino, or R^(3b), R^(4b) and the nitrogen atomto which they are attached form an alicyclic amino group selected fromthe group consisting of morpholino, 1-piperazinyl,4-methyl-1-piperazinyl, 1-pyrrolidinyl and piperidino.